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ID 117829
Title Alternative
腰部脊柱管狭窄症の肥厚した黄色靭帯の背側で筋線維芽細胞は増加している
Author
Hayashi, Fumio Tokushima University
Higashino, Kosaku Shikoku Medical Center for Children and Adults KAKEN Search Researchers
Goda, Yuichiro National Hospital Organization Kochi Hospital
Keywords
Myofibroblasts
Ligamentum flavum
Hypertrophy
Lumbar canal stenosis
Fibrosis
Collagen
Gene analysis
Histology
Lumbar spinal canal stenosis
Content Type
Thesis or Dissertation
Description
BACKGROUND CONTEXT: Hypertrophy of the ligamentum flavum (LF) is a major contributor to the development of lumbar spinal canal stenosis (LSS). Although previous studies have identified some factors related to hypertrophy of the LF, the etiology remains unclear. It is well known that myofibroblasts have a key role in the pathology of fibrosis in other tissues, including the skin, liver, kidney, and lung. We hypothesized that myofibroblasts were also important players in the pathology of fibrosis in the LF.
PURPOSE: To elucidate the distribution and role of myofibroblasts in the hypertrophic LF.
STUDY DESIGN: A histological, immunohistochemical, and gene expression analysis of the LF in the human lumbar spine.
PATIENT SAMPLE: Hypertrophic LF tissue samples were collected from patients with LSS.
OUTCOME MEASURES: Histology, immunohistochemistry, microarray, reverse transcription-quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay.
METHODS: The degree of fibrosis in the dural and dorsal layers of the LF was evaluated by Masson’s trichrome tissue staining. Collagen gene expression was evaluated by quantitative reverse transcription polymerase chain reaction. Immunostaining of αSMA was performed to evaluate localization of myofibroblasts in LF tissue. The association between gene expression of alpha-smooth muscle actin (αSMA) and that of several types of collagen was investigated. The signal activated on the dorsal side of LF was examined by gene set enrichment analysis using microarray data. Expression levels of αSMA and several types of collagen in LF fibroblasts were investigated under hypoxic conditions.
RESULTS: In the histological study using Masson’s trichrome staining, the fibrosis score was significantly higher in the dorsal layer than in the dural layer. Gene expression levels for several types of collagen (COL1A1, COL1A2, COL3A1, COL5A1, COL6A1, and COL11A1) and heat shock protein 47 (a collagen-specific chaperone) were significantly higher in the dorsal layer. Furthermore, immunohistochemistry revealed a significantly greater number of αSMA-stained cells in the dorsal layer. There was a strong correlation of αSMA mRNA expression with COL1A-1 in LF fibroblasts. Gene set enrichment analysis showed that the set of fibrosis-related gene signals, including those for epithelial-mesenchymal transition, hypoxia, and inflammation, were significantly upregulated in the dorsal layer compared with the dural layer. Under hypoxic stimulation, expression of αSMA and several types of collagen was increased in LF fibroblasts.
CONCLUSIONS: This study is the first to reveal that myofibroblast expression levels are higher in the dorsal layer of the LF than in the dural layer. We confirmed that hypertrophy of the LF in LSS is associated with increased expression of myofibroblasts in the dorsal layer. Hypoxia could be a cause of expression of myofibroblasts leading to fibrosis and finally to hypertrophy of the LF.
CLINICAL SIGNIFICANCE: The results of this study partially elucidate the molecular mechanisms of LF hypertrophy and suggest that myofibroblasts may be involved in age-related degeneration of the LF.
Journal Title
The Spine Journal
ISSN
15299430
18781632
NCID
AA11563339
AA11644135
Publisher
Elsevier|North American Spine Society
Volume
22
Issue
4
Start Page
697
End Page
704
Published Date
2021-11-11
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Fumio Hayashiの学位論文として提出され,学位審査・授与の対象となっている。
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3667号
Diploma Number
甲医第1549号
Granted Date
2022-11-24
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences